Circadian Features of Cluster Headache and Migraine

Abstract

Background and objectives:Cluster headache and migraine have circadian features at multiple levels (cellular, systems, and behavioral). A thorough understanding of their circadian features informs their pathophysiologies.Methods:A librarian created search criteria in Medline Ovid, Embase, PsycINFO, Web of Science, and Cochrane Library. Two physicians independently performed the remainder of the systematic review/meta-analysis using PRISMA guidelines. Separate from the systematic review/meta-analysis we performed a genetic analysis for genes with a circadian pattern of expression (Clock Controlled Genes or CCGs) by cross-referencing genome-wide association studies (GWAS) of headache, a non-human primate study of CCGs in a variety of tissues, and recent reviews of brain areas relevant in headache disorders. Altogether, this allowed us to catalog circadian features at the behavioral level (circadian timing, time of day, time of year, and chronotype), systems level (relevant brain areas where CCGs are active, melatonin and corticosteroid levels), and cellular level (core circadian genes and CCGs).Results:For the systematic review and meta-analysis, 1513 studies were found and 72 met inclusion criteria; for the genetic analysis we found 16 GWAS, 1 non-human primate study, and 16 imaging reviews.Cluster headache:Behaviorally, meta-analyses showed a circadian pattern of attacks in 70.5% (3490/4953) of participants across 16 studies, with a clear circadian peak between 21:00-03:00 and circannual peaks in spring and autumn. Chronotype was highly variable across studies. At the systems level, lower melatonin and higher cortisol levels were reported. At the cellular level, cluster headache was associated with core circadian genesCLOCKandREV-ERBα, and five of the nine cluster headache susceptibility genes were CCGs.Migraine:Behaviorally, meta-analyses showed a circadian pattern of attacks in 50.1% (2698/5385) of participants across eight studies, with a clear circadian trough between 23:00-07:00 and a broad circannual peak between April-October. Chronotype was highly variable across studies. At the systems level, urinary melatonin levels were lower in migraine participants and even lower during an attack. At the cellular level, migraine was associated with core circadian genesCK1δandRORα, and 110 of the 168 migraine susceptibility genes were CCGs.Discussion:Cluster headache and migraine are highly circadian at multiple levels, reinforcing the importance of the hypothalamus. This review provides a pathophysiological foundation for circadian-targeted research into these disorders.Trial Registration Information:The study was registered with PROSPERO (registration number CRD42021234238).

Circadian Factors in Cluster Headache and Migraine

“…As previously documented for cluster headache, this meta-analysis 6 found that a circadian pattern of attack was prominent, noted in 70.5% cases; attacks most commonly occur during the evening, with a peak at 2 AM. A circadian pattern also featured in 50.1% of participants with migraine, with most attacks occurring during the day, between late morning and early afternoon.…”

“…Hypothalamic activation plays a role in both types of headache, 2,3 and given the role of the hypothalamus in regulating both circadian and headache-relevant homeostatic functions in the brain, it is perhaps not surprising that some headache disorders display circadian features and may be underpinned by chronobiological factors. 4,5 In this issue of Neurology ® , Benkli et al 6 present a systematic literature review and meta-analysis of the current knowledge of a variety of circadian features in relation to cluster headache and migraine, including observations of headache chronobiology, circadian-associated hormonal and gene expression of susceptibility loci across tissues, and associated genetic variants in core clock genes.…”

“…Furthermore, the number of papers that have examined chronobiological factors in these headache disorders is still relatively few and many are underpowered for the number of participants to make statistically robust findings. Nevertheless, the meta-analysis of Benkli et al 6 is an important resource which synthesizes the current evidence from various lines of investigation to highlight relationships with the circadian cycle, and a role for the hypothalamus, in these headache disorders. Notwithstanding the challenges of more longitudinal monitoring, larger studies where these factors are considered, as well as investigating the possible benefits of circadian-based therapies, are required.…”

“…Alterations to circadian functions may be mediated by genetic variation in the core clock genes themselves. Benkli et al 6 have collated the studies reporting results for association tests of common genetic variants in clock genes or their transcript levels; most findings are of small effect and yet to be sufficiently replicated. Genome-wide association studies with large sample sizes provide an unbiased and more statistically robust set of genetic loci, and while core clock genes are not among the migraine or cluster headache susceptibility loci identified to date, the present study provides evidence that many genes implicated in each disorder are, nevertheless, clock-controlled, with rhythmic circadian expression in a range of tissues and importantly in relevant brain areas.…”

“…Genome-wide association studies with large sample sizes provide an unbiased and more statistically robust set of genetic loci, and while core clock genes are not among the migraine or cluster headache susceptibility loci identified to date, the present study provides evidence that many genes implicated in each disorder are, nevertheless, clock-controlled, with rhythmic circadian expression in a range of tissues and importantly in relevant brain areas. 6 The finding that rare sequence variants in the core clock protein CK1δ cause familial advanced-phase sleep syndrome, which co-occurs with migraine, in 2 independent pedigrees, provides intriguing genetic evidence that an underlying circadian malalignment can cause a migraine-associated disorder. 7 Studies using Mendelian randomization have also found a shared genetic basis and causal relationships between some sleep traits (insomnia, difficulty waking) and migraine.…”